We thank the National Institutes of Health (GM067726) and the Vanderbilt Institute of Chemical Biology for their support of this research. We also thank Joseph Reibenspies (Center for Chemical Characterization and Analysis, Texas A&M University) for the X-ray crystallographic analysis of 25. We gratefully acknowledge Prof. Mary Garson (University of Queensland) for providing a sample of dihydrohaliclonacyclamine C and spectral data. We also acknowledge Matthew Mulder and Chris Denicola (Lindsley Group, Vanderbilt University) for providing valuable analytical support.

Keywords:

alkaloids;

macrocycles;

natural products;

ring-closing metathesis;

total synthesis

First in its class: The synthesis of the tetracyclic alkylpiperidine marine alkaloid (±)-haliclonacyclamine C has been completed, with a longest linear sequence of 24 steps. The key transformations are the stereoselective hydrogenation of an unsaturated macrocyclic bis(piperidine) and a ring-closing alkyne metathesis reaction.